Autoimmune diseases are presumed to be initiated by a breach in self tolerance. This breakdown in the usually tightly regulated homeostatic mechanisms may involved multiple interactions between different cell types. One approach to the treatment of autoimmune disease might be to use a specific molecule to interfere with pathways that are involved in this pathologic process at multiple levels. A potential candidate target is the signal transducer and activator of transcription (STAT)-6, which is a molecule that is activated through the interleukin-4 (IL-4) receptor. Our laboratory has recently developed a series of small synthetic organic molecules, termed imidazobenzoithiazole (IBT) compounds, which have anti-STAT-6 biological activity. The specific aims of this proposal are: (i) To characterize in detail the mechanisms of action of imidazobenzoithiazole (IBT) compounds. (ii) To evaluate whether pharmacologic blockade of IL-4 by IBT induces Th biased immune responses. (iii) To determine whether the disruption of STAT-6 signaling by IBT affects the pathogenesis in a murine model of spontaneous autoimmune disease. The long-term goal of these studies is to develop a selective small molecule inhibitor as a therapeutic agent for the treatment of autoimmune diseases.